Introduction of nitrogen into natural products and biologically active small molecules has the potential to drastically change the physical and biological properties of a given molecule. For example, ampicillin, the first broad-spectrum penicillin derivative, differs from penicillin G by the presence of a benzylic amine (FIG. 1a). In fact, the importance of nitrogen in the benzylic position of pharmacophores can be gleaned by its appearance in top-selling FDA-approved drugs such as imatinib, meclizine, clopidogrel, sertraline, rivastigmine and donepezil, as well as many others. In nature, such nitrogen functionality is installed through oxygenated intermediates. For example, in the biosynthesis of 1-p-hydroxyphenylglycine, a crucial component of several peptidic natural products, the benzylic amine is installed from the benzylic ketone. Analogously, standard synthetic methods to install nitrogen rely on functional group transformations from pre-oxidized carbon-heteroatom (C—O, C—X, X=halogens) precursors. This approach limits the direct installation of nitrogen into topologically and functionally complex molecules, often necessitating de novo syntheses. The ability to effect late-stage functionalization via direct and selective installation of nitrogen in complex molecules may expedite discovery processes for biologically active small molecules and re-invigorate the exploration of natural-product-derived drug candidates.
Significant reactivity and selectivity challenges exist in the late-stage C—H amination of natural products and pharmaceuticals, as many similar C—H bond types may be present in a molecule. Noble-metal rhodium catalysis via metallonitrene intermediates is well established for the intramolecular C—H amination of a wide range of C—H bond types. One advantage of proceeding via metallonitrene intermediates is that both C—H cleavage and functionalization are tightly regulated at the metal and therefore are amenable to tuning via ligand/metal modifications. Intermolecular rhodium-catalyzed C—H aminations are emerging for benzylic, tertiary and allylic C—H aminations; however, chemo- and site-selectivity challenges exist in molecules with multiple reactive functionalities or C—H bonds. For example, in molecules with both tertiary and benzylic C—H bonds, inseparable product mixtures are formed (FIG. 1b). Moreover, the ability to effect remote C—H amination in molecules with basic amines or heterocyclic functionality has not been demonstrated for this type of C—H amination (FIG. 1c). Tertiary amine-containing natural products undergo α-amination/oxidation sequences to give amidines or direct N-amination to furnish hydrazine sulfamate zwitterions, with protection of nitrogen as an amine salt not shown to be tolerated.
Base-metal catalysts have emerged for highly selective intramolecular C—H aminations; however, analogous intermolecular processes are scarce. For example, cobalt-catalyzed intermolecular benzylic C—H aminations are not suitable for late-stage applications as they have formidable reactivity challenges requiring solvent quantities of substrates (FIG. 1d), and intramolecular processes do not appear to discriminate between C—H bonds based on electronic properties (FIG. 1e). Copper-catalyzed processes can have significant site- and chemoselectivity issues, furnishing mixtures of aminated products with substrates as simple as ethylbenzene. Iron- and manganese-catalyzed intermolecular C—H azidations have been reported to have tolerance for nitrogen heterocyclic functionality, but these proceed via free-radical pathways that result in poor site selectivities and long-lived substrate radicals that scramble the stereochemistry and may lead to skeletal rearrangements (FIG. 1f).
Accordingly, there is a need for a reagent that can selectively catalyze intermolecular C—H aminations in the presence of other functionalities.